NRLP3 Inhibitor VTX3232 Well-Tolerated, Improves Parkinson Symptoms in Phase 2a Trial

Late-breaking data from a phase 2 trial (NCT06556173), presented at the 2025 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held October 5-9, in Honolulu, Hawaii, showed that once daily administration of VTX3232 (Ventyx Biosciences), an investigational oral NLRP3 inhibitor, was safe and associated with improvement in both motor and nonmotor symptoms in patients with early-stage Parkinson disease (PD).¹

Presented by lead author Richard Gregg, MD, managing member of REGregg Consulting LLC, VTX3232 was well-tolerated with no drug-related treatment-emergent adverse events (AEs) among 10 patients with early PD. Notably, all reported AEs were considered mild or moderate in severity. Additionally, VTX3232 was associated with improvement on the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) in both motor and nonmotor symptoms of PD (Part I mean, -2.4, P = .0118; Part II mean, -2.7, P = .0471; Part III mean, -5.2, P = .0054).

This single-center, open-label phase 2a study assessed the safety, pharmacokinetics, and pharmacodynamic activity of a 40-mg oral daily dose of VTX3232 in patients with early-stage PD over a 28-day treatment period, using safety as the primary end point. Secondary assessments included pharmacokinetics, pharmacodynamic effects on NLRP3-related biomarkers, as well as exploratory evaluation of PD symptoms using MDS-UPDRS. Prior to the trial, previously completed phase 1 studies in healthy adults showed that doses of at least 12-mg of VTX3232 achieved therapeutic concentrations in plasma and CSF.

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“This was a thorough and well-conducted trial demonstrating clear evidence of target engagement in the cerebrospinal fluid (CSF) and plasma, with significant reduction to near-normal levels or the limit of quantitation in downstream biomarkers of NLRP3 inhibition, including IL-1b, IL-6 and high-sensitivity C-reactive protein,” principal investigator David Russell, MD, PhD, member of the Yale University Parkinson’s Disease Research Group, said in a statement.² “Our investigators also noted clinically significant reductions in MDS-UPDRS Parts II and III. With the caveat that this was a small, open-label study, all patients reported a subjective sense of improvement. Exploratory microglial PET imaging revealed no acute changes - not unexpected given the short duration of the trial.”

At steady state, the mean VTX3232 concentration 24 hours post dose was 107.2 ng/mL in plasma and 30.4 ng/mL in CSF, exceeding the IC90 for NLRP3 inhibition (~9 ng/mL) by more than 3-fold. By 28 days, interleukin (IL)-1β and IL-18 levels were reduced by 14% to 52% in both plasma and CSF. Downstream biomarkers, including IL-6, C-reactive protein, and serum amyloid A, decreased by 29% to 70%, with the largest reductions observed in participants with elevated baseline values.

“Neuroinflammation is recognized as a potential trigger for neurodegenerative diseases. By inhibiting NLRP3-mediated cytokine production and inflammatory markers in the CNS, VTX3232 provides a unique opportunity for a disease-modifying therapy for PD,” Raju Mohan, PhD, chief executive officer at Ventyx Biosciences, said in a statement.² “We are delighted that this trial met its goals of establishing that treatment with VTX3232 was safe and well tolerated, with high exposure levels in CSF and clear reductions in NLRP3-related biomarkers in a PD patient population. We have initiated internal and external planning discussions for a placebo-controlled Phase 2 trial in PD and potentially in additional neurodegenerative disorders such as Alzheimer’s disease.”

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REFERENCES
1. Gregg R, Christianson C, Liu K, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of VTX3232, a CNS-penetrant NRLP3 inhibitor, in participants with early-stage Parkinson’s disease. Presented at: 2024 MDS Congress; October 5-9; Honolulu, Hawaii. LBA-12.
2. Ventyx Biosciences Announces Positive Top-Line Data from its Phase 2a Safety and Biomarker Trial Evaluating VTX3232 in Patients with Early-Stage Parkinson’s Disease. News release. June 17, 2025. Accessed October 15, 2025. https://ir.ventyxbio.com/news-releases/news-release-details/ventyx-biosciences-announces-positive-top-line-data-its-phase-2a